WO2014107744A1 - Vaccins de trimère d'enveloppe (env) de virus d'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci - Google Patents

Vaccins de trimère d'enveloppe (env) de virus d'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci Download PDF

Info

Publication number
WO2014107744A1
WO2014107744A1 PCT/US2014/010543 US2014010543W WO2014107744A1 WO 2014107744 A1 WO2014107744 A1 WO 2014107744A1 US 2014010543 W US2014010543 W US 2014010543W WO 2014107744 A1 WO2014107744 A1 WO 2014107744A1
Authority
WO
WIPO (PCT)
Prior art keywords
menv
hiv
subject
vaccine
seq
Prior art date
Application number
PCT/US2014/010543
Other languages
English (en)
Inventor
Dan H. Barouch
Joseph NKOLOLA
Original Assignee
Beth Israel Deaconess Medical Center, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2014203886A priority Critical patent/AU2014203886B2/en
Priority to MX2015008815A priority patent/MX2015008815A/es
Application filed by Beth Israel Deaconess Medical Center, Inc. filed Critical Beth Israel Deaconess Medical Center, Inc.
Priority to SG11201505229XA priority patent/SG11201505229XA/en
Priority to NZ710727A priority patent/NZ710727A/en
Priority to JP2015551842A priority patent/JP6357487B2/ja
Priority to CA2897059A priority patent/CA2897059C/fr
Priority to CN201480012440.7A priority patent/CN105263506B/zh
Priority to AP2015008634A priority patent/AP2015008634A0/xx
Priority to MYPI2015702187A priority patent/MY187152A/en
Priority to KR1020157021492A priority patent/KR102020758B1/ko
Priority to EA201591287A priority patent/EA030983B1/ru
Priority to EP14735323.9A priority patent/EP2983686A4/fr
Publication of WO2014107744A1 publication Critical patent/WO2014107744A1/fr
Priority to IL239805A priority patent/IL239805A/en
Priority to PH12015501526A priority patent/PH12015501526B1/en
Priority to ZA2015/05608A priority patent/ZA201505608B/en
Priority to HK16102466.3A priority patent/HK1214509A1/zh
Priority to AU2018200696A priority patent/AU2018200696B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C07K14/08—RNA viruses
    • C07K14/15—Retroviridae, e.g. bovine leukaemia virus, feline leukaemia virus human T-cell leukaemia-lymphoma virus
    • C07K14/155—Lentiviridae, e.g. visna-maedi virus, equine infectious virus, FIV, SIV
    • C07K14/16—HIV-1 ; HIV-2
    • C07K14/162—HIV-1 ; HIV-2 env, e.g. gp160, gp110/120, gp41, V3, peptid T, CD4-Binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • Vaccines that elicit cellular immune responses against viruses seek to reflect global viral diversity in order to effectively treat or prevent viral infection.
  • HlV human immunodeficiency virus
  • the highly variable Envelope protein (Env) is the primary target for neutralizing antibodies against HIV, and vaccine antigens may be tailored accordingly to elicit these antibody responses.
  • immunogens mimicking the trimeric structure of Env on the native HIV virion are actively being pursued as antibody-based HIV vaccines.
  • the stabilized trimers are heterotrimers.
  • the stabilized polypeptide heterotrimers may include two mosaic Env1 gp140 polypeptides (e.g., mEnv and/or mEnv+) each including an amino acid sequence having at least 90% identity (e.g.
  • At least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to, or the sequence of, SEQ ID NO: 1 or 2, and one clade C Env gp140 polypeptide (e.g., "cEnv” having SEQ I D NO: 3) including an amino acid sequence having at least 90% identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 3 (cEnv) (e.g., two mEnv and one cEnv; two mEnv+ and one cEnv; or one mEnv, one mEnv+, and one cEnv).
  • cEnv e.g., two mEnv and one cEnv; two mEnv+ and one cEnv; or one mEnv, one mEnv+, and one
  • the stabilized heterotrimers may include one mosaic Env1 gp140 polypeptide (e.g., mEnv and/or mEnv+) including an amino acid sequence having at least 90% identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 1 or 2, and two clade C Env gp140 polypeptides (e.g..
  • the stabilized heterotrimer includes a combination of two different mosaic Env1 sequences (e.g. one mEnv and two mEnv+; two mEnv and one mEnv+; or one mEnv, one mEnv+, and cEnv).
  • the stabilized heterotrimer includes cEnv and two of the same Env1 polypeptides (e.g., two mEnv and one cEnv; two mEnv+ and one cEnv). In other embodiments, the stabilized heterotrimer includes one cEnv and two different mosaic Env1 polypeptides (e.g., one cEnv, one mEnv, and one mEnv+). In yet other embodiments, the stabilized heterotrimer includes two cEnv polypeptides and one mosaic Env1 polypeptide (e.g., two cEnv and one mEnv; or two cEnv and one mEnv+).
  • stabilized gp140 Env trimers can be prepared in which one or two of the gp140 Env polypeptides in the trimer has a sequence of SEQ ID NO: 4 (mosaic gp140 Env2, "mEnv2”) or SEQ ID NO: 5 (mosaic gp140 Env3, "mEnv3").
  • said stabilized trimers have three gp140 polypeptides in which at least one (e.g., two or each) of the gp140 polypeptides includes an amino acid sequence having at least 90% identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 4 or 5.
  • mEnv2 or mEnv3 is modified in a similar manner to that of mEnv, mEnv+, or cEnv, which each possess a trimerization domain, as discussed herein beiow.
  • stabilized gp140 Env trimers can be prepared which have the following constituent polypeptides: one mEnv and two mEnv2; two mEnv and one mEnv2; one mEnv+ and two mEnv2: two mEnv+ and one mEnv2; one cEnv and two mEnv2; two cEnv and one mEnv2; one mEnv, one mEnv+.
  • the invention features a composition including a stabilized trimer of the first or second aspect.
  • the composition of the third aspect includes one or more different stabilized trimer(s).
  • the different stabilized trimer(s) has three gp140 polypeptides in which at least one (e.g. , two or each) of the gp140 polypeptides comprises an amino acid sequence having at least 90% identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NOs: 1 , 2, 3, 4 or 5.
  • the different stabilized trimer(s) may be a homotrimer or a heterotrimer.
  • the compositions of the third aspect further include a pharmaceutically acceptable carrier, excipient, or diluent, and/or an adjuvant.
  • the invention features a vaccine including any one of the compositions of the third aspect.
  • the vaccine is used for treating or reducing the risk of a human immunodeficiency virus (HIV) infection in a subject in need thereof.
  • the vaccine elicits production of neutralizing anti-HIV antisera (e.g., neutralizing anti-HIV-1 antisera) after administration to the subject.
  • the anti-HIV antisera can neutralize HIV (e.g., HIV-1 ), for example, selected from any one or more of clade A, clade B, and clade C.
  • the invention features a nucleic acid molecule having a nucleotide sequence that encodes at least one (e.g., two, or three or more) gp140 polypeptide, wherein the at least one gp140 polypeptide includes: (a) an amino acid sequence having at least 95% identity (e.g., at least 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 1 ; (b) an amino acid sequence having at least 95% identity (e.g., at least 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 2; or (c) an amino acid sequence having the sequence of SEQ ID NO: 3; (d) an amino acid sequence having the sequence of SEQ ID NO: 4; (e) an amino acid sequence having the sequence of SEQ ID NO: 5 or combinations thereof.
  • an amino acid sequence having at least 95% identity e.g., at least 96%, 97%, 98%, or 99% identity
  • the nucleic acid molecule further includes a nucleotide sequence that encodes one or more different (e.g., a second, third, or fourth) gp140 polypeptides (e.g., gp140 polypeptides having at least 95% identity (e.g., at least 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 1 , 2, 3, 4 and/or 5).
  • the nucleic acid molecule includes one or more internal ribosome entry site (IRES) sequences to allow for the expression of multiple peptide or polypeptide chains from the single nucleic acid molecule transcript.
  • IVS internal ribosome entry site
  • the invention features a vector including one or more nucleic acid molecules of the fifth aspect.
  • the vector is an adenovirus vector or a poxvirus vector.
  • the adenovirus vector may be derived, for example, from a recombinant adenovirus serotype 1 1 (Ad11 ), adenovirus serotype 15 (Ad15), adenovirus serotype 24 (Ad24), adenovirus serotype 26 (Ad26), adenovirus serotype 34 (Ad34), adenovirus serotype 35 (Ad 35), adenovirus serotype 48 (Ad48), adenovirus serotype 49 (Ad49), adenovirus serotype 50 (Ad 50), Pan9 (AdC68), or a chimeric variant thereof (e.g.. adenovirus serotype 5 HVR48 (Ad5HVR48)).
  • the poxvirus vector may be derived, for example, from a
  • the invention provides a method of treating or reducing the risk of an HIV infection in a subject in need thereof by administering a therapeutically effective amount of a composition of the invention (e.g., any one of the stabilized trimers of the first or second aspect, the compositions of the third aspect, the vaccines of the fourth aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect) to the subject, such as a mammal, for example, a human.
  • Treating can be therapeutic or prophylactic.
  • the invention provides a method of reducing an HIV-mediated activity in a subject infected with HIV by administering a therapeutically effective amount of a composition of the invention (e.g., any one of the stabilized trimers of the first or second aspect, the compositions of the third aspect, the vaccines of the fourth aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect) to the subject.
  • a composition of the invention e.g., any one of the stabilized trimers of the first or second aspect, the compositions of the third aspect, the vaccines of the fourth aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect
  • the HIV-mediated activity is viral spread, infection, or cell fusion. Cell fusion may be, for example, target cell entry or syncytial formation.
  • the HIV titer in the subject infected with HIV is decreased (e.g.
  • the composition (e.g., a vaccine) is administered intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleural ⁇ , intratracheal ⁇ , intranasally, intravitreally, intravaginally, intra rectaily, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularliy, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, by gavage, in cremes, or in lipid compositions.
  • the subject is administered at least one dose (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) of the composition or is administered at least one dose (e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) daily, weekly, monthly, or yearly.
  • the administration period may be defined (e.g. , 1-4 weeks, 1-12 months, 1-20 years) or may be for the life of the subject.
  • the subject is administered at least two doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses) of the composition.
  • the composition is administered to said subject as a prime or a boost composition or in a prime-boost regimen.
  • one or more composition(s) (e.g., a vaccine) of the invention is administered as a boost.
  • the prime composition in this prime-boost regimen may include polypeptide(s) having the sequence(s) of any one of SEQ ID NOs: 8-32, or one or more vectors including nucleic acid molecules that encode any one of SEQ ID NOs: 8-32, followed by a boost including one or more of the composition(s) of the invention (e.g., any one of the stabilized trimers of the first or second aspect, the compositions of the third aspect, the vaccines of the fourth aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect).
  • a boost including one or more of the composition(s) of the invention e.g., any one of the stabilized trimers of the first or second aspect, the compositions of the third aspect, the vaccines of the fourth aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect.
  • the subject can be administered at least about 1 x10 3 viral particles (vp)/dose or between 1x10 1 and 1x10 14 vp/dose, preferably between 1 x10 3 and 1x10 12 vp/dose, and more preferably between 1x10 s and 1x10 11 vp/dose.
  • vp viral particles
  • the composition may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 35, 40, 45, 50, 55, or 60 minutes, 2, 4, 6, 10, 15, or 24 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, or even 3, 4, or 6 months preexposure or pre-diagnosis, or may be administered to the subject 15-30 minutes or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 20, 24, 48, or 72 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, 3, 4, 6, or 9 months, 1 , 2, 3, 4, 5. 6, 7, 8, 9, 10, 15, 20 years or longer post-diagnosis or post-exposure or to HIV.
  • the subject is administered one or more doses of the composition once daily, weekly, monthly, or yearly.
  • composition(s) of the invention e.g., any one of the stabilized trimers of the first, second, or third aspect, the compositions of the fourth or fifth aspect, the vaccines of the sixth aspect, the nucleic acid molecules of the seventh aspect, and/or the vectors of the eighth aspect
  • AIDS acquired immune deficiency syndrome
  • composition(s) may be administered, for example, immediately after diagnosis or the ciinicai recognition of symptoms or 2, 4, 6, 10, 15, or 24 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, or even 3, 4, or 6 months after diagnosis or detection of symptoms.
  • the subject is a mammal, preferably a primate, such as a human.
  • adenovirus is meant a medium-sized (90-100 nm), non-enveloped icosahedral virus that includes a capsid and a double-stranded linear DNA genome.
  • the adenovirus can be a naturally occurring, but isolated, adenovirus (e.g., sAd4287, sAd4310A, or sAd4312) or a recombinant adenovirus (e.g. , replication-defective or replication competent sAc>4287, sAd4310A, or sAd4312, or a chimeric variant thereof).
  • administering is meant a method of giving a dosage of a pharmaceutical composition (e.g., a composition of the invention, such as any one of the vaccines of the first or fourth aspects, the compositions of the third aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect) to a subject.
  • a pharmaceutical composition e.g., a composition of the invention, such as any one of the vaccines of the first or fourth aspects, the compositions of the third aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect
  • the compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously,
  • intraarterially intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically,
  • the preferred method of administration can vary depending on various factors (e.g., the components of the composition being administered and the seventy of the condition being treated).
  • the term "ciade” refers to related human immunodeficiency viruses (HIVs) classified according to their degree of genetic similarity.
  • H!V-1 isolates There are currently three groups of H!V-1 isolates: M. N and O.
  • Group M major strains
  • Group O outer strains
  • Group N is a new HIV-1 isolate that has not been categorized in either group M or O.
  • a composition of the invention e.g.
  • any one of the vaccines of the first or fourth aspects, the compositions of the third aspect, the nucleic acid molecules of the fifth aspect, and/or the vectors of the sixth aspect) as described herein will recognize and raise an immune response (e.g., neutralizing anti-HIV antisera) against two, three, four, five, six, seven, eight, nine, ten or more clades and/or two or more groups of HIV.
  • an immune response e.g., neutralizing anti-HIV antisera
  • envelope glycoprotein refers, but is not limited to, the glycoprotein that is expressed on the surface of the envelope of HIV virions and the surface of the plasma membrane of HIV infected cells.
  • the env gene encodes gp160, which is proteolytically cleaved into the gp120 and gp41 Envelope (Env) proteins.
  • Gp120 binds to the CD4 receptor on a target cell that has such a receptor, such as, e.g., a T-helper cell.
  • Gp41 is non-covalently bound to gp120, and provides the second step by which HIV enters the cell.
  • heterologous nucleic acid molecule or “heterologous gene” is meant any exogenous nucleic acid molecule (e.g.. a nucleic acid molecule encoding an optimized gp140 Env polypeptide of the invention) that can be inserted into the a vector of the invention (e.g., an adenovirus or poxvirus vector) for transfer into a cell, tissue, or organism, for subsequent expression of a gene product of interest or fragment thereof encoded by the heterologous nucleic acid molecule or gene.
  • a vector of the invention e.g., an adenovirus or poxvirus vector
  • the heterologous nucleic acid molecule which can be administered to a cell or subject as part of the present invention, can include, but is not limited to, a nucleic acid molecule encoding at least one optimized mosaic Env polypeptide (e.g., a mosaic Env1 polypeptide, such as mEnv and mEnv+) and/or a clade C Env polypeptide (e.g., a clade C Env1 polypeptide, such as cEnv).
  • a nucleic acid molecule encoding at least one optimized mosaic Env polypeptide (e.g., a mosaic Env1 polypeptide, such as mEnv and mEnv+) and/or a clade C Env polypeptide (e.g., a clade C Env1 polypeptide, such as cEnv).
  • HIV human immunodeficiency virus
  • HIV-1 HIV type 1
  • HIV-2 HIV type 2
  • immune response is meant any response to an antigen or antigenic determinant by the immune system of a subject (e.g., a human).
  • exemplary immune responses include humoral immune responses (e.g., production of antigen-specific antibodies, e.g.. neutralizing antibodies (NAbs)) and cell- mediated immune responses (e.g., lymphocyte proliferation).
  • humoral immune responses e.g., production of antigen-specific antibodies, e.g.. neutralizing antibodies (NAbs)
  • cell- mediated immune responses e.g., lymphocyte proliferation
  • reducing refers to a reduction or decrease of an HIV-mediated activity (e.g., infection, fusion ⁇ e.g., target cell entry and/or syncytia formation), viral spread, etc.) and/or a decrease in viral titer.
  • HIV-mediated activity and/or HIV titer may be decreased by 5%, 10%, 15%, 20%, 25%. 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 81 %, 82%. 83%.
  • sequence identity or ' sequence similarity is meant that the identity or similarity between two or more amino acid sequences, or two or more nucleotide sequences, is expressed in terms of the identity or similarity between the sequences. Sequence identity can be measured in terms of ' percentage (%) identity," wherein the higher the percentage, the more identity shared between the sequences.
  • trimerization domains include, but are not limited to, the T4- fibritin "foldon" trimerization domain; the coiled-coil trimerization domain derived from GCN4 (Yang et ai. (2002) J. Virol. 76:4634); and the catalytic subunit of E. coli aspartate transcarbamoylase as a trimer tag (Chen et al. (2004) J. Virol. 78:4508).
  • a subject to be treated according to the present invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors (e.g., a needle stick or known exposure to HIV or an HIV infected individual).
  • risk factors e.g., a needle stick or known exposure to HIV or an HIV infected individual.
  • having substantially the sequence of with respect to constructs of the invention is meant having at least 99% sequence identity to a recited reference sequence (e.g., having no more than 7 amino acid residue differences, e.g., 1 , 2, 3, 4, 5, or 6 amino acid residue differences (e.g., additions, deletions, or conservative amino acid substitutions), relative to a recited reference sequence).
  • a recited reference sequence e.g., having no more than 7 amino acid residue differences, e.g., 1 , 2, 3, 4, 5, or 6 amino acid residue differences (e.g., additions, deletions, or conservative amino acid substitutions), relative to a recited reference sequence).
  • therapeutically effective amount is meant an amount of a therapeutic agent that alone, or together with one or more additional (optional) therapeutic agents, produces beneficial or desired results upon administration to a mammal.
  • the therapeutically effective amount depends upon the context in which the therapeutic agent is applied.
  • the therapeutically effective amount of the vaccine composition is an amount sufficient to achieve a reduction in the levei of HIV (e.g., as measured by a stabilization or decrease in HIV titer compared to a non-treated control), and/or an increase in the level of neutralizing anti-HIV antisera (e.g., as measured by an increase in serum neutralizing antibody levels relative to a non-treated control in a luciferase-based virus neutralization assay) as compared to a response obtained without administration of a composition of the invention (e.g., a vaccine composition), and/or to prevent the propagation of an infectious virus (e.g., HIV) in a subject (e.g.
  • treatment is an approach for obtaining beneficial or desired results, such as clinical results.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilization (i.e., not worsening) of a state of disease, disorder, or condition; prevention of spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable, "Palliating 3 a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • vacun is defined as material used to provoke an immune response (e.g., the production of neutralizing anti-HIV antisera).
  • Administration of the vaccine to a subject may confer at least partial immunity against HIV infection.
  • vector is meant to include, but is not limited to, a virus (e.g., adenovirus or poxvirus), naked DNA, oligonucleotide, cationic lipid (e.g., liposome), cationic polymer (e.g., polysome), virosome, nanoparticle, or dentrimer.
  • a virus e.g., adenovirus or poxvirus
  • naked DNA oligonucleotide
  • cationic lipid e.g., liposome
  • cationic polymer e.g., polysome
  • virosome e.g., nanoparticle, or dentrimer.
  • adenovirus vector is meant a composition that includes one or more genes (non-structural or structural), or fragments thereof, from an adenoviral species (e.g., adenovirus serotype 1 1 (Ad1 1 ), adenovirus serotype 15 (Ad15), adenovirus serotype 24 (Ad24), adenovirus serotype 26 (Ad26), adenovirus serotype 34 (Ad34), adenovirus serotype 35 (Ad35), adenovirus serotype 48 (Ad48), adenovirus serotype 49 (Ad49), adenovirus serotype 50 (Ad50), Pan9 (AdC68), or a chimeric variant thereof (e.g., adenovirus serotype 5 HVR48 (Ad5HVR48))) that may be used to transmit one or more heterologous genes (e.g., one or more of the optimized gp140 polypeptides of the
  • the nucleic acid material of the viral vector may be encapsulated, e.g., in a lipid membrane or by structural proteins (e.g., capsid proteins), that may include one or more viral polypeptides (e.g., an envelope glycoprotein).
  • the virai vector can be used to infect cells of a subject, which, in turn, promotes the translation of the heterologous gene(s) of the viral vector into a protein product (e.g., one or more of the gp140 Env polypeptides described herein, such that a stabilized trimer of the invention is formed).
  • SEQ ID NO: 2 SEQ ID NO: 2 of the invention.
  • This polypeptide sequence has been further optimized and includes a different signal/leader sequence to maximize protein expression (boxed region); the addition of cleavage site-inactivating mutations (E/E substitution mutations) (circled residues); and the addition of a Factor Xa site (zig-zag underlined region). Other regions are noted as in Figure 1A.
  • Figure 2 is a Western blot showing the expression levels of mEnv and mEnv+ in lanes 3 and 4. respectively, compared to cEnv and an expression vector control (pVRC8400) in lanes 1 and 2.
  • Figure 5C is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with both cEnv and mEnv trimers tested against a multi-clade panel of tier 1 neutralization-sensitive isolates including clade B (SF162.LS and Bal.26) and clade C (MWSS5.26 and TV1.21) HIV-1 Envelope pseudoviruses. as well as Murine lukemia virus (MuLV) (negative control).
  • Pre pre-vaccination
  • Post post-vaccination
  • cEnv and mEnv trimers tested against a multi-clade panel of tier 1 neutralization-sensitive isolates including clade B (SF162.LS and Bal.26) and clade C (MWSS5.26 and TV1.21) HIV-1 Envelope pseudoviruses. as well as Murine lukemia virus (MuLV) (negative control).
  • Figure 6A is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization-sensitive clade A HIV-1 Envelope pseudovirus, MS208.A1.
  • Figure 7A is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 A highly neutralization-sensitive clade B HIV-1 Envelope pseudovirus, SF162.LS.
  • Figure 7C is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization-sensitive clade B HIV-1 Envelope pseudovirus, SS1196.1.
  • Figure 7D is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer. or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization-sensitive clade B HIV-1 Envelope pseudovirus, 6535.3.
  • Figure 8B is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization-sensitive clade C HIV-1 Envelope pseudovirus, TV1.21.
  • Figure 8C is a graph showing a quantitative analysis of ID 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) with cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization-sensitive clade C HIV-1 Envelope pseudovirus, ZM109F.PB4.
  • Figure 8D is a graph showing a quantitative analysis of iD 50 titer measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post) cEnv homotrimer, mEnv homotrimer, or both cEnv and mEnv trimers tested against a Tier 1 B intermediate neutralization- sensitive clade C HIV-1 Envelope pseudovirus, ZM197M.PB7.
  • Figure 9B is a graph showing the size-exclusion chromatography profile of purified mEnv.
  • Figure 9C is a graph showing the size exclusion chromatography profile of mEnv after freeze- thaw and incubation at 4°C for 7 days. The signals for freeze-thaw and 4°C incubation for 7 days overlap closely.
  • Figure 10B is a graph showing the SPR binding profile of mEnv to 17b IgG. 17b IgG was captured and mEnv trimer flowed over bound IgG at a concentration of 1000 nM in the presence (gray trace) or absence (black trace) of CD4 bound to the immunogen.
  • Figures 10C and 10D are graphs showing the SPR binding profiles of mEnv to VRC01 and
  • FIG. 1A - 1 1 F are graphs showing the SPR binding profiles of mEnv to glycan-dependent bnAbs PGT121 , PGT126 and quaternary dependent bnAbs PG9 and PG16.
  • protein A was irreversibly coupled to a CM5 chip and IgGs were captured.
  • Figure 12C is a set of graphs showing 2F5 and 4E10 binding ELISA of mEnv. Both mEnv (mosaic gp140) and mosaic gp120 show no detectable signal. Clade A (92UG037.8) intermediate-gp41 (Frey et al. (2008) Proc. Natl. Acad. Sci. U.S.A. 105:3739) (positive control) is presented as squares, mEnv is presented as triangles. Dotted line indicates assay background threshold.
  • Figure 13 is a graph showing mEnv pseudovirion infection of TZM.bi cells. Pseudovirions generated with full length mosaic M gp160 Env were used to infect target TZM.bi cells expressing CD4 and co-receptors CCR5/CXCR4 in the TZM.bi assay. Broken horizontal line indicates background of TZM.bi ceils alone without virus (negative control). RLU, relative luminescence units.
  • Figures 15A and 15B are graphs showing neutralizing antibody titers against panels of tier 1 HIV- 1 isolates in the TZM.bi assay, using Matrix M adjuvant. Sera obtained post-third-trimer vaccination in cEnv (C), mEnv (M), or bivalent cEnv + mEnv (C+M) vaccinated guinea pigs were tested against a multi- clade panel of tier 1 (MW965.26, SF162.
  • Figures 15C and 15D are graphs showing neutralizing antibody titers against panels of tier 1 HIV- 1 isolates in the TZM.bi assay, using CpG/Emulsigen adjuvant.
  • Sera obtained post-third-trimer vaccination in cEnv (C), mEnv (M), or bivalent cEnv + mEnv (C+M) vaccinated guinea pigs were tested against a multi-clade panel of tier 1 (MW965.26, SF162.LS, Bal.26, DJ263.8, TV1 .21 , MS208, Q23.17, SS1 196.1 , 6535.3, ZM109.
  • Figures 16A and 16B are graphs showing neutralizing antibody titers of guinea pig sera against HIV-1 tier 2 clade B and C isolates in the A3R5 neutralization assay.
  • Sera obtained pre-vaccination (Pre) and post-third-trimer vaccination (Post) in Matrix M adjuvanted cEnv, rnEnv or bivalent cEn + mEnv (C+ ) vaccinated guinea pigs were tested against (A) tier 2 clade C isolates Ce_1086_B2.
  • Broken horizontal line indicates assay background threshold. * P ⁇ 0.05; Mann-Whitney test.
  • Figure 17A is a graph showing robust purity of the optimized version of mosaic M gp140 referred to as "mEnv+" in a 2-liter fresh preparation.
  • Figure 17B is a graph showing robust stability of mEnv+ after freeze/thaw or incubation at 4°C for 1 week. The signals for freeze-thaw and 4°C incubation for 7 days overlap closely.
  • Figure 7C is an SDS-PAGE gel showing robust stability of mEnv+ after freeze/thaw or incubation at 4 degrees C for 1 week.
  • Figure 19 is a set of graphs showing quantitative analyses of !D 50 titers, measuring TZM.bl neutralizing antibody responses in guinea pigs pre-vaccination (Pre) and post-vaccination (Post). mEnv and mEnv+ showed comparable immunogenicity in these assays regardless of adjuvant.
  • the invention features novel stabilized HIV gp140 Env polypeptide trimers.
  • Stabilized trimers of the invention feature optimized gp140 Env polypeptides. These polypeptides may have, or may be modified to include, one or more of the following domains and/or mutations.
  • the gp140 Env polypeptide constituents may include a T4- fibritin "foldon" trimerization domain sequence to support stable trimer formation (see, e.g., Figures 1A, 1 B, and 1 C, depicting the amino acid sequences of mEnv (SEQ ID NO: 1 ), mEnv+ (SEQ ID NO: 2), and cEnv (SEQ ID NO: 3), respectively, which each include a C-terminal trimerization domain).
  • the optimized gp140 Env polypeptides may also include cleavage site mutations to enhance stability, for example, by eliminating cleavage by a peptidase (see, e.g., Figures 1 B and 1 C, which depict the mutated residues as circled residues in the mEnv+ and cEnv amino acid sequence, respectively, between the gp120 and gp41 moieties).
  • the optimized gp140 Env polypeptides may additionally have a signal/leader sequence to maximize protein expression (see, e.g. , the signal/leader sequence of mEnv+ or cEnv, demarcated in Figures 1 B and 1 C, respectively).
  • the optimized gp140 Env polypeptides may include a Factor Xa cleavage site (SRIEGR), which may, for example, be incorporated upstream of (N-terminal to) the trimerization domain (see, e.g., Figures 1 B and 1 C, which depict the location of the Factor Xa cleavage site in the amino acid sequence of mEnv+ and cEnv, respectively).
  • SRIEGR Factor Xa cleavage site
  • the stabilized trimers of the invention are preferably homotrimers (e.g., trimers composed of three identical polypeptides).
  • Heterotrimers e.g., trimers composed of three polypeptides that are not all identical) of the invention are also envisioned.
  • the stabilized trimers of the invention are preferably stabilized homotrimers that include, for example, three gp140 polypeptides, wherein each of the gp140 polypeptides includes an amino acid sequence having at least 90% identity (e.g., at least 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 2 (mEnv+).
  • the invention also features stabilized homotrimers including three gp140 polypeptides, wherein each of said gp140 polypeptides includes an amino acid sequence having substantially the sequence of (e.g., 99% or more identity), or the sequence of, SEQ ID NO: 1 (mEnv) or SEQ ID NO: 3 (cEnv) or SEQ ID NO: 4 or SEQ ID NO: 5.
  • Exemplary homotrimers of the invention include Trimers 1 , 2. and 3 in Table 1 below.
  • the stabilized trimer of the invention may be a stabilized heterotrimer.
  • the stabilized trimer may be a stabilized heterotrimer that includes a combination of two different mosaic Envl sequences (e.g., one mEnv and two niEnv+; two mEnv and one mEnv+; or one mEnv, one mEnv+, and cEnv).
  • the stabilized heterotrimer includes cEnv and two of the same En l polypeptides (e.g., two mEnv and one ctnv; two mbnv+ and one cEnv).
  • the stabilized heterotrimer includes one cEnv and two different mosaic Envl polypeptides (e.g., one cEnv, one mEnv, and one mEnv+).
  • the stabilized heterotrimer may include one, two or three constituent Env polypeptides including an amino acid sequence of SEQ ID NO: 4 (mosaic gp140 Env2, "mEnv2”) or SEQ ID NO: 5 (mosaic gp140 Env3, "mEnv3").
  • mEnv2 or mEnv3 is modified in a similar manner to that of mEnv, mEnv+, or cEnv, which each possess a trimerization domain, as discussed above and as depicted in Figures 1A-1 C.
  • other stabilized heterotrimers of the invention include trimers having the following constituent polypeptides: one mEnv and two mEnv2; two mEnv and one mEnv2; one mEnv+ and two mEnv2; two mEnv+ and one mEnv2; one cEnv and two mEnv2; two cEnv and one mEnv2; one mEnv, one mEnv+, and one mEnv2; one mEnv, one cEnv, and mEnv2; one mEnv+, one cEnv, and one mEnv2; one mEnv and two mEnv3; two mEnv and one mEnv3; one mEnv+ and two mEnv3; two mEnv+ and one mEnv3; one cEnv and two mEnv3; one cEnv and two mEnv3; one mEnv, one mEnv,
  • compositions may include a stabilized homotrimer including three mosaic Env1 polypeptides, for example, three polypeptides of mEnv or three polypeptides of mEnv+ or three optimized clade C Env polypeptides, such as the cEnv polypeptide of SEQ ID NO: 3.
  • the compositions may also include a stabilized heterotrimer.
  • the composition e.g., a vaccine
  • other vaccines of the invention may include stabilized heterotrimers having the following constituent polypeptides: one mEnv and two mEnv2; two mEnv and one mEnv2: one mEnv+ and two mEnv2; two mEnv+ and one mEnv2; one cEnv and two mEnv2; two cEnv and one mEnv2; one mEnv, one mEnv+, and one mEnv2: one mEnv, one cEnv, and mEnv2; one mEnv+, one cEnv, and one mEnv2; one mEnv and two mEnvS; two mEnv and one mEnv3; one mEnv+ and two mEnv3; two mEnv+ and one mEnv3; one cEnv and two mEnvS; two cEnv and one mEnvS; two cEnv and one mEnv
  • compositions of the invention may further include a pharmaceutically acceptable carrier, excipieni, or diluent, and/or an adjuvant.
  • a pharmaceutically acceptable carrier excipieni, or diluent, and/or an adjuvant.
  • the invention features vaccines including at least one of the compositions of the invention described herein and above.
  • the vaccine may be used for treating or reducing the risk of a human immunodeficiency virus (HIV) infection in a subject in need thereof.
  • the vaccine may elicit production of neutralizing anti-HIV antisera (e.g., neutralizing anti-HIV- 1 antisera) after administration to the subject.
  • neutralizing anti-HIV antisera e.g., neutralizing anti-HIV- 1 antisera
  • the anti-HIV antisera may also be able to neutralize HIV (e.g., HIV-1 ), for example, selected from any one or more of clade A, clade B, and clade C.
  • the vaccines of the invention include one or more nucleic acid molecules of the invention, such as a nucleic acid molecule having a nucleotide sequence that encodes a gp140 polypeptide, in which the gp140 polypeptide includes (a) an amino acid sequence having at least 95% identity (e.g. , 96%, 97%, 98%, 99%, or 100% identity) to SEQ ID NO: 1 , (b) an amino acid sequence having at least 95% identity (e.g., 96%, 97%, 98%, 99%, or 100%. identity) to SEQ ID NO: 2, and/or (c) an amino acid sequence having the sequence of SEQ ID NO: 3, (d) an amino acid sequence having the sequence of SEQ ID NO: 4.
  • a nucleic acid molecule having a nucleotide sequence that encodes a gp140 polypeptide in which the gp140 polypeptide includes (a) an amino acid sequence having at least 95% identity (e.g. , 96%, 97%
  • the stabilized gp140 Env trimer polypeptides of the invention can be recombinantly expressed in a cell or organism, or can be directly administered to a subject (e.g., a human) infected with, or at risk of becoming infected with, HIV (e.g., HiV-1).
  • a subject e.g., a human
  • HIV e.g., HiV-1
  • the invention features vectors including one or more of the nucleic acid molecules of the invention.
  • the vector can be, for example, a carrier (e.g., a liposome), a plasmid, a cosmid, a yeast artificial chromosome, or a virus (e.g., an adenovirus vector or a poxvirus vector) that includes one or more of the nucleic acid molecules of the invention.
  • Vectors of the invention can be constructed using any recombinant molecular biology technique known in the art.
  • The' vector upon transfection or transduction of a target cell or organism, can be extrachromosomai or integrated into the host celt chromosome.
  • the nucleic-acid component of a vector can be in single or multiple copy number per target cell, and can be linear, circular, or concatamerized.
  • the vectors can also include internal ribosome entry site (IRES) sequences to allow for the expression of multiple peptide or polypeptide chains from a single nucleic acid transcript (e.g., a polycistronic vector, e.g., a bi- or tri-cistronic vector).
  • IVS internal ribosome entry site
  • Vectors of the invention can also include gene expression elements that facilitate the expression of the encoded polypeptide(s) of the invention (e.g., SEQ ID NOs: 1 (mEnv), 2 (mEnv+), 3 (cEnv), 4 and/or 5 or polypeptides having amino acids sequences with at least 90%, 91 %, 92$, 93&, 94%, 95%, 96%, 97%, 98%), or 99% sequence identity to SEQ ID NO: 1 or 2).
  • gene expression elements that facilitate the expression of the encoded polypeptide(s) of the invention (e.g., SEQ ID NOs: 1 (mEnv), 2 (mEnv+), 3 (cEnv), 4 and/or 5 or polypeptides having amino acids sequences with at least 90%, 91 %, 92$, 93&, 94%, 95%, 96%, 97%, 98%), or 99% sequence identity to SEQ ID NO: 1 or 2).
  • Recomoinant adenoviruses offer several significant advantages for use as vectors for the expression of, for example, one or more of the optimized gp140 Env polypeptides of the invention.
  • the viruses can be prepared to high titer, can infect non-replicating cells, and can confer high-efficiency transduction of target cells ex vivo following contact with a target cell population.
  • adenoviruses do not integrate their DNA into the host genome. Thus, their use as expression vectors has a reduced risk of inducing spontaneous proliferative disorders. In animal models, adenoviral vectors have generally been found to mediate high-level expression for approximately one week.
  • transgene expression expression of a nucleic acid molecule of the invention
  • duration of transgene expression can be prolonged by using cell or tissue-specific promoters.
  • Other improvements in the molecular engineering of the adenovirus vector itself have produced more sustained transgene expression and less inflammation. This is seen with so-called “second generation” vectors harboring specific mutations in additional early adenoviral genes and "gutless" vectors in which
  • adenovirus serotype 11 (Ad11 ), adenovirus serotype 15 (Ad15), adenovirus serotype 24 (Ad24), adenovirus serotype 25 (Ad26), adenovirus serotype 34 (Ad34), adenovirus serotype 35 (Ad35), adenovirus serotype 48 (Ad48), adenovirus serotype 49 (Ad49), adenovirus serotype 50 (Ad50).
  • Ad11 recombinant adenovirus serotype 11
  • Ad15 adenovirus serotype 15
  • Ad24 adenovirus serotype 24
  • Ad26 adenovirus serotype 25
  • Ad34 adenovirus serotype 34
  • Ad35 adenovirus serotype 35
  • Ad48 adenovirus serotype 48
  • Ad49 adenovirus serotype 50
  • Ad50 adenovirus serotype 50
  • AAV Adeno-Associated Virus
  • Adeno-associated viruses derived from non-pathogenic parvoviruses, can also be used to facilitate delivery and/or expression of one or more of the optimized gp140 Env polypeptides of the invention as these vectors evoke almost no anti-vector cellular immune response, and produce transgene expression lasting months in most experimental systems.
  • Stabilized trimers of the invention may be produced upon expression of the gp140 Env polypeptides described herein using an AAV vector.
  • Retroviruses include lentiviruses, a family of viruses including human immunodeficiency virus (HIV) that includes several accessory proteins to facilitate viral infection and proviral integration.
  • HIV human immunodeficiency virus
  • Current, “third-generation, " lenrivira! vectors feature total replication incompetence, broad tropism, and increased gene transfer
  • Stabilized trimers of the invention may be produced upon expression of the gp140 Env polypeptides described herein using a retrovirus vector.
  • viral vectors and techniques are known in the art that can be used to facilitate delivery and/or expression of one or more of the optimized gp140 Env polypeptides of the invention in a cell (e.g., a blood cell, such as a lymphocyte) or subject (e.g., a human) in order to promote formation of the trimers of the invention.
  • viruses include poxviruses (e.g., vaccinia virus and modified vaccinia virus Ankara (MVA); see, e.g., U.S. Patent Nos.
  • herpesviruses e.g., Venezuelan Equine Encephalitis virus; see, e.g., U.S. Patent No. 5,643,576, incorporated by reference herein
  • picornaviruses e.g., poiiovirus; see, e.g., U.S. Patent No. 5.635,649. incorporated by reference herein
  • bacuioviruses and others described by Wattanapitayakul and Bauer [Bio mod. Pharmacotner. 54:487 (2000), incorporated by reference herein).
  • Naked DNA or oligonucleotides encoding one or more of the optimized gp140 Env polypeptides of the invention can also be used to express these polypeptides in a cell or a subject (e.g., a human) in order to promote formation of the trimers of the invention.
  • a subject e.g., a human
  • lipoplexes e.g., liposomes
  • polyplexes can be used to protect the nucleic acid from undesirable degradation during the transfection process.
  • the nucleic acid molecules can be covered with lipids in an organized structure like a micelle or a liposome. When the organized structure is complexed with the nucleic acid molecule it is called a lipoplex.
  • lipids anionic (negatively- charged), neutral, or cationic (positively-charged).
  • Lipoplexes that utilize cationic lipids have proven utility for gene transfer. Cationic lipids, due to their positive charge, naturally complex with the negatively- charged nucleic acid. Also as a result of their charge they interact with the cell membrane, endocytosis of the lipoplex occurs, and the nucieic acid is released into the cytoplasm. The cationic lipids also protect against degradation of the nucleic acid by the cell.
  • polyplexes Complexes of polymers with nucleic acids are called po!yplexes.
  • Most polyplexes consist of cationic polymers and their production is regulated by ionic interactions.
  • One large difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot release their nucleic acid load into the cytoplasm, so, to this end, co-transfection with endosome-lytic agents (to lyse the endosome that is made during endocytosis) such as inactivated adenovirus must occur.
  • endosome-lytic agents to lyse the endosome that is made during endocytosis
  • polymers such as polyethylenimine have their own method of endosome disruption as does chitosan and trimethy!chitosan.
  • Exemplary cationic lipids and polymers that can be used in combination with one or more of the nucleic acid molecules encoding one or more of the optimized gp140 Env polypeptides of the invention to form lipoplexes or polyplexes include, but are not limited to, polyethylenimine, lipofectin, lipofectamine, polylysine, chitosan, trimethylchitosan, and alginate.
  • Virosomes for example, combine lipoplexes (e.g., liposomes) with an inactivated virus. This approach has been shown to result in more efficient gene transfer in respiratory epithelial cells compared to either virai or liposomal methods alone.
  • Other methods involve mixing other viral vectors with cationic lipids or hybridizing viruses. Each of these methods can be used to facilitate transfer of one or more of the nucleic acid molecules of the invention encoding one or more of the optimized gp140 Env polypeptides of the invention into a cell or subject in order to promote formation of the trimers of the invention.
  • the method may be used to treat or reduce the risk of an HIV infection in a subject in need thereof.
  • the subject may be infected with HIV or may be at risk of exposure to HIV.
  • the compositions of the invention can be administered to a subject infected with HIV to treat AIDS.
  • compositions of the invention may also be administered in the form of a vaccine for prophylactic treatment of a subject (e.g., a human) at risk of an HIV infection.
  • a subject e.g., a human
  • compositions utilized in the methods described herein can be formulated, for example, for administration intramuscularly, intravenously, intradermal ⁇ , percutaneously, intraarterial ⁇ ,
  • intraperitoneal ⁇ intralesionally, intracranially, intraarticular ⁇ , intraprostatically, intrapleural ⁇ , intratracheal ⁇ , intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival ⁇ , intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, by gavage, in cremes, or in lipid compositions.
  • the preferred method of administration can vary depending on various factors (e.g., the components of the composition being administered and the severity of the condition being treated).
  • compositions of the invention may be administered to provide pre-infection prophylaxis or after a subject has been diagnosed with an HIV infection or a disease with an etiology traceable to an HIV infection (e.g., AIDS).
  • the composition may be administered, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 35, 40, 45, 50, 55, or 60 minutes, 2, 4, 6, 10, 15, or 24 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, or even 3, 4, or 6 months pre-infection or pre-diagnosis, or may be administered to the subject 15-30 minutes or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 20, 24, 48, or 72 hours, 2, 3, 5, or 7 days, 2, 4, 6 or 8 weeks, 3, 4, 6, or 9 months, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 years or longer post-diagnosis or post-infection to H!V.
  • the boost in this regimen includes one or more of the composition(s) of the invention (e.g., any one of the stabilized trimers, the compositions, the vaccines, the nucleic acid molecules, and/or the vectors of the invention).
  • the prime includes at least a first vector including a nucleic acid molecule that encodes a polypeptide having the sequence of any one of SEQ ID NOs: 8-32.
  • the composition (e.g., vaccine) of the invention is administered as a prime.
  • a different vaccine e.g., a vaccine including at least a first vector including a first nucleic acid molecule that encodes a polypeptide having at least 85% amino acid sequence identity (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 6, and optionally a second vector including a second nucleic acid molecule that encodes a polypeptide having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% -identity) to, or the sequence of, SEQ iD NO: 7; or a vaccine including at least a first vector including a nucleic acid molecule that encodes a
  • the subject may be administered, in the form of a virai vector, at least about 1x10° viral particles (vp)/dose or between 1x10 1 and 1x10 14 vp/dose, preferably between 1x10 3 and 1x10 12 vp/dose. and more preferably between 1x10 5 and 1x10 1 i vp/dose.
  • vp 1x10° viral particles
  • Viral particles include nucleic acid molecules encoding one or more of the optimized gp140 Env polypeptides of the invention and are surrounded by a protective coat (a protein-based capsid with hexon and fiber proteins). Viral particle number can be measured based on, for example, lysis of vector particles, followed by measurement of the absorbance at 260 nm (see, e.g.. Steel, Curr. Opin. Biotech., 1999).
  • the dosage administered depends on the subject to be treated (e.g., the age, body weight, capacity of the immune system, and general health of the subject being treated), the form of
  • composition is preferably administered in an amount that provides a sufficient level of the stabilized gp140 Env trimer gene product (e.g., a level of stabilized gp140 Env trimer that elicits an immune response without undue adverse physiological effects in the subject caused by the immunogenic trimer).
  • a sufficient level of the stabilized gp140 Env trimer gene product e.g., a level of stabilized gp140 Env trimer that elicits an immune response without undue adverse physiological effects in the subject caused by the immunogenic trimer.
  • single or multiple administrations of the compositions of the present invention may be given (pre- or post-infection and/or pre- or post-diagnosis) to a subject (e.g., one administration or administration two or more times).
  • subjects who are particularly susceptible to, for example, HIV infection may require multiple treatments to establish and/or maintain protection against the virus.
  • Levels of induced immunity provided by the pharmaceutical compositions described herein can be monitored by, for example, measuring amounts of neutralizing anti-HIV secretory and serum antibodies.
  • the dosages may then be adjusted or repeated as necessary to trigger the desired level of immune response.
  • the immune response triggered by a single administration (prime) of a composition of the invention may not be sufficiently potent and/or persistent to provide effective protection.
  • repeated administration such that a prime-boost regimen is established, may significantly enhance humoral and cellular responses to the antigen of the composition.
  • a single dose of one or more of the compositions of the invention may achieve protection, pre- infection or pre-diagnosis.
  • a single dose administered post-infection or post-diagnosis can function as a treatment according to the present invention.
  • a single dose of one or more of the compositions of the invention can also be used to achieve therapy in subjects being treated for a disease. Multiple doses (e.g., 2, 3, 4, 5, or more doses) can also be administered, in necessary, to these subjects.
  • compositions of the invention may be prepared using standard methods known in the art by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences (20 th edition), ed. A. Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, PA).
  • Acceptable carriers include saline, or buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagines, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, PLURONICSTM, or PEG.
  • buffers such as phosphate, citrate and other organic acids
  • antioxidants including ascorbic acid
  • low molecular weight (less than about 10 residues) polypeptides such as serum albumin, gelatin or
  • the formulation contains a pharmaceutically acceptable salt, preferably sodium chloride, and preferably at about physiological concentrations.
  • the formulations of the invention can contain a pharmaceutically acceptable preservative.
  • the preservative concentration ranges from 0.1 to 2.0%, typically v/v.
  • Suitable preservatives include those known in the pharmaceutical arts. Benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben are preferred preservatives.
  • the formulations of the invention can include a pharmaceutically acceptable surfactant at a concentration of 0.005 to 0.02%.
  • compositions of the invention can be formulated to include, be administered concurrently with, and/or be administered in series with one or more pharmaceutically acceptable adjuvants to increase the immunogenicity of the composition (e.g., upon administration to a subject in need thereof, e.g., a subject infected with HIV or at risk of an HIV infection).
  • adjuvants approved for human use include aluminum salts (alum). These adjuvants have been useful for some vaccines including hepatitis B, diphtheria, polio, rabies, and influenza.
  • CFA Complete Freund's Adjuvant
  • IFA Incomplete Freund's Adjuvant
  • MDP muramyl dipeptide
  • MTP- PE Adju-Phos
  • Matrix M CpG/Emulsigen
  • compositions containing a metabolizable oil and an emulsifying agent wherein the oil and emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than one micron in diameter.
  • the present invention also provides for the ex vivo transfection or transduction of cells, followed by administration of these cells back into a subject (e.g., human) to allow for the expression of one or more of the optimized gp140 Env polypeptides of the invention that have immunogenic properties, in one embodiment, the cells are autologous to the treated subject.
  • Cells can bs transfected or transouced ex vivo v/ith, for example, one or more vectors of the invention to allow for the temporal or permanent expression of one or more of the optimized gp140 Env polypeptides in the treated subject.
  • the one or more vectors of the invention Upon administering these modified cells to the subject, the one or more vectors of the invention will be expressed, eliciting protective or therapeutic immune responses (e.g., cellular or humoral immune responses, e.g., production of neutralizing anti-HIV antisera) directed against the gp140 immunogenic trimer or trimers that form.
  • protective or therapeutic immune responses e.g., cellular or humoral immune responses, e.g., production of neutralizing anti-HIV antisera
  • Cells that can be isolated and transfected or transduced ex vivo according to the methods of invention include, but are not limited to, blood cells, skin cells, fibroblasts, endothelial cells, skeletal muscle cells, hepatocytes, prostate epithelial cells, and vascular endothelial cells.
  • Stem cells are also appropriate cells for transduction or transfection with a vector of the invention.
  • Totipotent, pluripotent, multipotent, or unipotent stem cells including bone marrow progenitor cells and hematopoietic stem cells (HSC)
  • HSC hematopoietic stem cells
  • US Provisional Application No. 61/886,932 incorporated herein by reference in its entirety, discloses HIV ciade C Env trimers, the polypeptides of which may be used in combination with polypeptides disclosed herein to form trimers of the present invention.
  • US Provisional Application No. 61/884,414, also incorporated herein by reference discloses methods of treating subjects infected with HIV and blocking HIV infections in subjects at risk of HIV infection using H332 glycan-dependent antibodies.
  • PCT application WO 2012/030904 also incorporated herein by reference in its entirety, discloses broadly neutralizing antibodies against HIV, any of which can be used in methods of treating HIV in a subject in need thereof according to the present invention.
  • Exemplary antibodies include VRC01 , PGT121 , PGT126, PG9, PG16, and 3BNC1 17.
  • volumes containing 10-pg equivalents of DN.A expression vectors pVRC8400 empty, pVRC8400 mosaic gpl40 version-1 (expression vector for a polypeptide including the amino acid sequence of SE.Q ID NO: 1 ), or pVRC ' 8400 mosaic gp140 version-2 (expression vector for a polypeptide including the amino acid sequence of SEQ ID NO: 2) were each made up to 100 ⁇ with Dulbeco's Modified Eagle Medium (DMEM; invitrogen). 40 ⁇ ! of Lipofectamine (invitrogen) transfection reagent was then added 60 ⁇ ! DMEM and 100 ⁇ of this mix added to each DNA vector followed by gentle agitation and incubation at room temperature for 30 minutes.
  • DMEM Dulbeco's Modified Eagle Medium
  • 293T cells grown to approximately 70-80% confluency in T-25 flasks were washed once with 2.5 mi DMEM, 2.3 ml of DMEM added followed by 200 ⁇ DNA/Lipofectamine mix. Cells were then incubated at 37°C, 10% C0 2 for 48 hours. 48 hours post-transfection, 0.5ml of supernatant from each T-25 flask was harvested, briefly spun and 20 ⁇ placed in a fresh eppendorf tube. 5 ⁇ of 5x reducing sample buffer (Pierce) was added to each tube, each sample heated for 5 minutes at 100°C and then place on ice to cool.
  • 5x reducing sample buffer Pieris
  • DNA expression vector pVRC8400 mosaic gp140 version-2 250 pg of DNA expression vector pVRC8400 mosaic gp140 version-2 was mixed with 320 ⁇ of poiyethyienimine (PEi) (1 mg/ml) added to 20 ml of room temperature freestyie 293 medium, incubated at room temperature for 20 minutes and then added in each roller bottle followed by incubation for 6 days in 37°C, 5% C0 2. The cell supernatant was harvested at 6 days after medium change.
  • the Histidine- tagged optimized mosaic gp140 Env version-2 protein, including SEQ ID NO: 2 was purified by Ni-NTA (Qiagen) followed by size-exclusion chromatography.
  • the cell supernatant was loaded onto a nickel column at a flow rate of 0.8 mL/min and was washed with 20 mM imidazole in PBS followed by further washing with 40 mM imidazole in PBS.
  • the protein then was eluted with 300 mM imidazole in PBS.
  • the fractions containing the purified protein were pooled, concentrated, and further purified by gel-filtration
  • Guinea pigs were immunized by bilateral intramuscular injections in the upper quadriceps with clade C gp140 Env polypeptide (i.e., homotrimer of three molecules including the amino acid sequence of cEnv (SEQ ID NO: 3)), mosaic gp140 Env (i.e., homotrimer of three molecules including the amino acid sequence of mEnv (SEQ ID NO: 1 )), or a ciade C gp140 Env/mosaic gp140 Env mixture (100 pg/animal) at 4-week intervals (weeks 0, 4, and 8) using 500 pi of a dual adjuvant combination comprising 15% (v/v) oil-in-water Emulsigen (MVP Laboratories)/PBS and 50 g of immunostimulatory di- nucle
  • Virus was added to each well in a volume of 50pl, and the plates were incubated for 1 hour at 37 °C. Then TZM.bl cells were added (1x10 4 per well in 100 pi volume) in 10% DMEM growth medium containing diethylaminoethyldextran (Sigma) at a final concentration of 11 ⁇ g/m ⁇ .
  • Murine leukemia virus (MuLV) negative controls were included in all assays.
  • HIV-1 Envelope pseudoviruses included c!ade A (MS208.A1 and Q23.17) isolates, clade B (SF162.LS, BaL.26. SS1 196.1 and 6535.3), and clade C (MW965.26, TV1.21 , ZM109F.PB4 and Z 97M.PE7) isolates.
  • mEnv+ (polypeptide including the amino acid sequence of SEQ ID NO: 2) has been modified from mEnv (polypeptide including the amino acid sequence of SEQ ID NO: 1 ) in the following manner.
  • the leader peptide secretion sequence has been made identical to that used in the stabilized clade C gp140 Env (cEnv) trimer polypeptide constituent (SEQ ID NO: 3).
  • cleavage site mutations have been incorporated between gp120 and gp41 moieties to further enhance stability.
  • a factor Xa protease cleavage site (SRIEGR) has been incorporated upstream of the foldon trimerization domain.
  • SRIEGR factor Xa protease cleavage site
  • Figure 2 depicts a Western blot showing the expression levels of mEnv and mEnv+ in ianes 3 and 4, respectively. otably, the expression ieveis of mEnv-i- were remarkably higher compared to that of mEnv or cEnv, which was used as a positive control (see lane 1). In this experiment, empty pVRC8400 was used as a negative control (see lane 2).
  • the mEnv+ was expressed in 293T cells and purified following cell lysis and clarification by virtue of a His-tag using a Ni-NTA (Qiagen) column.
  • the collected fractions following imidazole elution were pooled, concentrated, and further purified by gel-filtration chromatography on Superose 6 (GE Healthcare) in a column running buffer containing 25 mM Tris (pH 7.5) and 150 mM NaCI.
  • a chromatography trace of depicting mEnv+ elution from the Superose 6 column is depicted in Figure 3.
  • the peak fractions (i.e., the fractions obtained under the peak curve in Figure 3) were then individually analyzed on a 4-15% pre-case SDS-PAGE gel ( Figure 4).
  • the SDS-PAGE gel demonstrates that the gel-filtration purification successivefully resulted in the isolation of a homogenous population of mEnv+ polypeptides.
  • the immunogenicity of these stabilized gp140 Env trimers both homotrimers of mEnv and mEnv+, as well as a combination of mEnv and cEnv homotrimers was assessed in guinea pigs using a panel of tier 1 isolates from clades A, B, and C.
  • Example 4 Treating or reducing the risk of an HIV infection in a subject using the compositions of the invention
  • the subject Prior to administration of the boost, the subject is administered as a prime vaccination at least a first vector including a first nucleic acid molecule that encodes a polypeptide having at least 85% amino acid sequence identity (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 6, and optionally a second vector including a second nucleic acid molecule that encodes a polypeptide having at least 85% identity (e.g., 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to, or the sequence of, SEQ ID NO: 7.
  • a first vector including a first nucleic acid molecule that encodes a polypeptide having at least 85% amino acid sequence identity (e.g., 86%, 87%
  • the patient can be assessed for changes in one or more symptoms or, in particular, the level of HIV titer in the treated subject, and the regimen can be repeated as necessary as described herein above.
  • the synthetic gene for full-length mosaic M gp120 with a C-terminal His-tag was generated from the mEnv construct by PCR amplification with custom primers, produced in 293T cells utilizing transient transfections with polyethylenimine and subsequently purified by Ni-NTA (Qiagen) and size-exclusion chromatography on Superdex 200 (GE Healthcare).
  • the PVDF membrane was incubated for 1 hour with PBS T containing a 1 :2000 dilution of monoclonal antibody penta His-HRP (Qiagen), washed 5 times with PBS-T and developed using the Amersham ECL plus Western blotting detection system (GE Healthcare).
  • clade A 92UG037.8
  • gp140 Kovacs et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109:121 11 ; Nkoloia et al. (2010) J. Virol. 84:3270
  • mosaic M gp140 proteins were processed as above.
  • SPR Surface plasmon resonance
  • Adjuvants co-administered with the proteins were a previously described combination comprising 15% (vol/vol) oil-in-water Emulsigen (MVP Laboratories)/PBS and 50 pg of immunostimulatory di-nucleotide type B oCpG DNA (5'-TCGTCGTTGTCGTTTTGTCGTT-3') (Midland Reagent Company) (Kovacs et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109: 121 11 ) or the
  • Tier 2 nAb responses were evaluated using the A3R5 assay as previously described (Kovacs et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109: 121 1 1 ). Briefly, serial dilutions of serum samples were performed in 10% RPMI growth medium (100 pL per well) in 96-well flat-bottomed plates. IMC HIV-1 expressing Renilla luciferase (Edmonds et al. (2010) Virology. 408: 1 ) was added to each well in a volume of 50 ⁇ , and plates were incubated for 1 hour at 37°C.
  • Binding rate constants derived from surface plasmon resonance (SPR) analyses. Binding kinetics were fitted with the Langmuir 1 : 1 binding model.
  • PG9 and PG16 bind preferentially to intact Env trimers and target N-linked glycans and variable loops 1 and 2 (V1 V2) and N-linked glycans in this region (Walker et al. (2009) Science. 326:285, McLellan et al. (2011 ) Nature. 480:336).
  • the mosaic gp120 monomer bound with a 22-fold lower affinity and substantially lower magnitude (1 ,280 nM) (Table 2; Figure 11 E).
  • tier 1 psuedoviruses comprising easy-to-neutraiize tier 1A viruses (SF1S2.LS, MW955.26) and an extended panel of intermediate tier 1 B viruses (DJ263.8, Bai.26, TV1.21 , MS208, Q23.17, SS119.6.1 , .6535.3, ZM109.F,

Abstract

La présente invention concerne des trimères d'enveloppe (Env) de virus d'immunodéficience humaine (VIH) stabilisés. L'invention concerne en outre des vaccins, des acides nucléiques, et des vecteurs pour délivrer et/ou faciliter la production des trimères d'Env de VIH stabilisés. La présente invention concerne en outre des procédés de fabrication et d'utilisation des trimères d'Env de VIH stabilisés de l'invention en tant que vaccins.
PCT/US2014/010543 2013-01-07 2014-01-07 Vaccins de trimère d'enveloppe (env) de virus d'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci WO2014107744A1 (fr)

Priority Applications (17)

Application Number Priority Date Filing Date Title
MYPI2015702187A MY187152A (en) 2013-01-07 2014-01-07 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using same
AP2015008634A AP2015008634A0 (en) 2013-01-07 2014-01-07 Stabilized human immunodeficiency virus 'hiv' env elope 'env' trimer vaccines and methods of using same
SG11201505229XA SG11201505229XA (en) 2013-01-07 2014-01-07 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using the same
NZ710727A NZ710727A (en) 2013-01-07 2014-01-07 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using the same
JP2015551842A JP6357487B2 (ja) 2013-01-07 2014-01-07 安定化ヒト免疫不全ウイルス（ｈｉｖ）エンベロープ（ｅｎｖ）トリマーワクチン及びそれを使用する方法
CA2897059A CA2897059C (fr) 2013-01-07 2014-01-07 Vaccins de trimere d'enveloppe (env) de virus d'immunodeficience humaine (vih) stabilises et procedes d'utilisation de ceux-ci
CN201480012440.7A CN105263506B (zh) 2013-01-07 2014-01-07 稳定的人免疫缺陷病毒(HIV)包膜(EnV)三聚体疫苗及其使用方法
AU2014203886A AU2014203886B2 (en) 2013-01-07 2014-01-07 Stabilized human immunodeficiency virus (HIV) envelope (Env) trimer vaccines and methods of using the same
MX2015008815A MX2015008815A (es) 2013-01-07 2014-01-07 Vacunas de trimero del envolvente (env) del virus de la inmunodeficiencia humana (vih) estabilizadas y metodos de usarlas.
EA201591287A EA030983B1 (ru) 2013-01-07 2014-01-07 ВАКЦИНЫ, СОДЕРЖАЩИЕ СТАБИЛИЗИРОВАННЫЕ ТРИМЕРЫ ОБОЛОЧКИ (Env) ВИРУСА ИММУНОДЕФИЦИТА ЧЕЛОВЕКА (ВИЧ), И СПОСОБЫ ИХ ПРИМЕНЕНИЯ
KR1020157021492A KR102020758B1 (ko) 2013-01-07 2014-01-07 안정화된 사람 면역결핍 바이러스 (ｈｉｖ) 외피 (ｅｎｖ) 삼량체 백신 및 이의 사용 방법
EP14735323.9A EP2983686A4 (fr) 2013-01-07 2014-01-07 Vaccins de trimère d'enveloppe (env) de virus d'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci
PH12015501526A PH12015501526B1 (en) 2013-01-07 2015-07-06 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using same
IL239805A IL239805A (en) 2013-01-07 2015-07-06 Trimer vaccines with the HIV virus envelope are stabilized
ZA2015/05608A ZA201505608B (en) 2013-01-07 2015-08-04 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using the same
HK16102466.3A HK1214509A1 (zh) 2013-01-07 2016-03-03 穏定的人類免疫缺陷病毒 包膜蛋白基因 三聚體疫苗及其使用方法
AU2018200696A AU2018200696B2 (en) 2013-01-07 2018-01-30 Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361749737P 2013-01-07 2013-01-07
US61/749,737 2013-01-07

Publications (1)

Publication Number Publication Date
WO2014107744A1 true WO2014107744A1 (fr) 2014-07-10

Family

ID=51062514

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/010543 WO2014107744A1 (fr) 2013-01-07 2014-01-07 Vaccins de trimère d'enveloppe (env) de virus d'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci

Country Status (18)

Country Link
US (4) US9932370B2 (fr)
EP (1) EP2983686A4 (fr)
JP (1) JP6357487B2 (fr)
KR (1) KR102020758B1 (fr)
CN (1) CN105263506B (fr)
AP (1) AP2015008634A0 (fr)
AU (2) AU2014203886B2 (fr)
CA (1) CA2897059C (fr)
EA (1) EA030983B1 (fr)
HK (1) HK1214509A1 (fr)
IL (1) IL239805A (fr)
MX (1) MX2015008815A (fr)
MY (1) MY187152A (fr)
NZ (1) NZ710727A (fr)
PH (1) PH12015501526B1 (fr)
SG (2) SG11201505229XA (fr)
WO (1) WO2014107744A1 (fr)
ZA (1) ZA201505608B (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016049287A1 (fr) 2014-09-26 2016-03-31 Beth Israel Deaconess Medical Center, Inc. Méthodes et compositions d'induction d'une immunité protectrice contre l'infection par le virus de l'immunodéficience humaine
KR20170122711A (ko) * 2014-10-03 2017-11-06 로스 알라모스 내셔널 씨큐어리티 엘엘씨 하나 이상의 집단 에피센서스 항원을 포함하는 hiv 백신 조성물
WO2017216288A1 (fr) 2016-06-16 2017-12-21 Janssen Vaccines & Prevention B.V. Formulation de vaccin contre le vih
WO2018229711A1 (fr) 2017-06-15 2018-12-20 Janssen Vaccines & Prevention B.V. Vecteurs à poxvirus codant pour des antigènes du vih, et leurs procédés d'utilisation
WO2019018724A1 (fr) 2017-07-21 2019-01-24 Janssen Vaccines & Prevention B.V. Procédés d'induction sûre d'une immunité croisée multiclades contre une infection par le virus de l'immunodéficience humaine chez l'être humain
WO2019055888A1 (fr) 2017-09-18 2019-03-21 Janssen Vaccines & Prevention B.V. Méthodes pour induire une réponse immunitaire contre une infection par le virus de l'immunodéficience humaine chez des sujets subissant un traitement antirétroviral
US10307477B2 (en) 2016-09-02 2019-06-04 Janssen Vaccines & Prevention B.V. Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment
US10369214B2 (en) 2015-12-15 2019-08-06 Janssen Vaccines & Prevention B.V. Synthetic human immunodeficiency virus (HIV) envelope antigen, vectors, and compositions thereof
WO2020064621A1 (fr) 2018-09-25 2020-04-02 Janssen Vaccines & Prevention B.V. Méthode d'induction d'une réponse immunitaire contre le virus de l'immunodéficience humaine par administration co-localisée de composants vaccinaux
US10653770B2 (en) * 2008-10-10 2020-05-19 Beth Israel Deaconess Medical Center, Inc. Biochemically stabilized HIV-1 Env trimer vaccine
US10793607B2 (en) 2016-09-15 2020-10-06 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
WO2020237052A1 (fr) 2019-05-22 2020-11-26 Janssen Vaccines & Prevention B.V. Procédés pour induire une réponse immunitaire contre une infection par le virus de l'immunodéficience humaine chez des sujets suivant un traitement antirétroviral
US10968254B2 (en) 2017-07-19 2021-04-06 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
WO2021089770A2 (fr) 2019-11-07 2021-05-14 Janssen Vaccines & Prevention B.V. Purification de protéines
WO2023198815A1 (fr) 2022-04-14 2023-10-19 Janssen Vaccines & Prevention B.V. Administration séquentielle d'adénovirus

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9090673B2 (en) 2003-12-12 2015-07-28 City Of Hope Synthetic conjugate of CpG DNA and T-help/CTL peptide
CA2897059C (fr) 2013-01-07 2021-12-28 Beth Israel Deaconess Medical Center, Inc. Vaccins de trimere d'enveloppe (env) de virus d'immunodeficience humaine (vih) stabilises et procedes d'utilisation de ceux-ci
US10376583B2 (en) 2013-09-30 2019-08-13 Beth Israel Deaconess Medical Center, Inc. Human immunodeficiency virus therapies utilizing N332-glycan-dependent antibodies and a reservoir activator
US10716845B2 (en) 2013-10-04 2020-07-21 Beth Israel Deaconess Medical Center, Inc. Stabilized human immunodeficiency virus (HIV) clade C envelope (Env) trimer vaccines and methods of using same
EP3110953A1 (fr) * 2014-02-28 2017-01-04 Janssen Vaccines & Prevention B.V. Vecteurs adénoviaux recombinés se répliquant, compositions et procédés pour les utiliser
KR102019572B1 (ko) 2014-07-11 2019-09-06 길리애드 사이언시즈, 인코포레이티드 Hiv의 치료를 위한 톨-유사 수용체의 조정제
US20180271973A1 (en) * 2014-12-24 2018-09-27 Duke University Compositions comprising ch505 envelopes, and trimers (eight valent hiv-1 composition and methods)
WO2016196471A1 (fr) 2015-06-02 2016-12-08 Cooper Human Systems Llc Procédés et compositions pour le traitement d'une infection par le vih
CN115925910A (zh) * 2016-03-09 2023-04-07 马萨诸塞大学 经修饰的hiv-1用于产生完全人抗体的用途
WO2017192434A1 (fr) 2016-05-02 2017-11-09 The Scripps Research Institute Compositions et procédés associés à des immunogènes du vih-1
WO2018075559A1 (fr) 2016-10-17 2018-04-26 Beth Israel Deaconess Medical Center, Inc. Vaccins contenant un trimère d'enveloppe (env) du virus de l'immunodéficience humaine (vih) à base de signatures et procédés d'utilisation de ceux-ci
WO2019089817A1 (fr) * 2017-11-01 2019-05-09 The Scripps Research Institute Nouveaux immunogènes vaccinaux anti-vih-1 de type échafaudage
US11845788B2 (en) 2018-05-22 2023-12-19 Beth Israel Deaconess Medical Center, Inc. Antibody therapies for human immunodeficiency virus (HIV)
JP2021527077A (ja) 2018-06-13 2021-10-11 ザ スクリプス リサーチ インスティテュート 新規構造成分を含有するナノ粒子ワクチン
WO2021146272A1 (fr) * 2020-01-13 2021-07-22 The Regents Of The University Of California Procédés de traitement d'infections virales
WO2022005214A1 (fr) * 2020-06-30 2022-01-06 포항공과대학교 산학협력단 Kit de criblage pour agent thérapeutique pour une maladie à coronavirus employant une activité estérase de protéine de spicule de virus de covid-19, et utilisation de la substance criblée en employant d'un kit pour la prévention, l'atténuation ou le traitement d'une maladie à coronavirus

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4603112A (en) 1981-12-24 1986-07-29 Health Research, Incorporated Modified vaccinia virus
US5639649A (en) 1989-01-18 1997-06-17 Brtish Technology Group Limited Attenuated viruses
US5643576A (en) 1994-05-27 1997-07-01 The University Of North Carolina At Chapel Hill Method of inducing an immune response with a live Venezuelan Equine Encephalitis virus expressing a heterologous immunogen
US5762938A (en) 1991-03-07 1998-06-09 Virogenetics Corporation Modified recombinant vaccinia virus and expression vectors thereof
WO2006040330A2 (fr) 2004-10-13 2006-04-20 Crucell Holland B.V. Vecteurs adenoviraux ameliores et leurs utilisations
WO2007024941A2 (fr) 2005-08-23 2007-03-01 The Regents Of The University Of California Vaccin polyvalent
WO2007104792A2 (fr) 2006-03-16 2007-09-20 Crucell Holland B.V. Adénovirus recombinés basés sur les sérotypes 26 et 48 et utilisation de ceux-ci
US7592014B2 (en) * 1999-06-25 2009-09-22 Progenics Pharmaceuticals Inc. Stabilized viral envelope proteins and uses thereof
WO2010059732A1 (fr) 2008-11-18 2010-05-27 Beth Israel Deaconess Medical Center Vaccins antiviraux présentant une immunogénicité cellulaire améliorée
US20110250220A1 (en) * 2006-10-23 2011-10-13 PROGENICS PHARMACEUTICAL: INC.: and CORNELL RESEARCH FOUNDATION INC. Modified gp140 envelope polypeptides of hiv-1 isolates, compositions, stabilized trimeric complexes, and uses thereof
US20120045472A1 (en) * 2008-10-10 2012-02-23 Beth Israel Deaconess Medical Center Biochemically Stabilized HIV-1 ENV Trimer Vaccine
WO2012030904A2 (fr) 2010-08-31 2012-03-08 Theraclone Sciences, Inc. Anticorps neutralisants anti-virus de l'immunodéficience humaine (vih)
WO2015048779A1 (fr) 2013-09-30 2015-04-02 Qualcomm Incorporated Communication par paquet court dans un réseau sur courants porteurs
WO2015051270A1 (fr) 2013-10-04 2015-04-09 Beth Israel Deaconess Medical Center, Inc. Vaccins de trimères d'enveloppe (env) de clade c du virus de l'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1214333A4 (fr) 1999-09-17 2005-01-19 Dana Farber Cancer Inst Inc Trimeres stabilises solubles de glycoproteines
WO2004044155A2 (fr) 2002-11-07 2004-05-27 Beth Israel Deaconess Medical Center Mip-1$g(a) et gm-csf adjuvants de la reponse immune
AU2003298912B2 (en) 2002-12-03 2011-06-02 Advanced Bioscience Laboratories, Inc. Polyvalent, primary HIV-1 glycoprotein DNA vaccines and vaccination methods
US20070298051A1 (en) 2003-11-19 2007-12-27 Beth Israel Deaconess Medical Center Adjuvants Of Immune Response
EP1766097A4 (fr) 2004-06-15 2008-03-19 Progenics Pharm Inc Anticorps de neutralisation du vih-1 elicites par un complexe trimerique de glycoproteines d'enveloppe du vih-1
EP1784416B1 (fr) 2004-07-16 2011-10-05 GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Vaccins contre le sida comprenant des constructions d'acides nucleiques cmv/r
CA2656741A1 (fr) 2005-07-06 2007-01-11 University Of Maryland Biotechnology Institute Immunogene a base d'enveloppe de vih de type limite presentant simultanement des sites de liaison de recepteur et de co-recepteur
US20110076298A1 (en) 2006-06-19 2011-03-31 Olson William C Soluble stabilized trimeric hiv env proteins and uses thereof
US20140348791A1 (en) 2011-09-09 2014-11-27 Beth Israel Deaconess Medical Center, Inc. Modified adenoviral vectors and methods of treatment using same
AU2012216792A1 (en) 2011-09-12 2013-03-28 International Aids Vaccine Initiative Immunoselection of recombinant vesicular stomatitis virus expressing HIV-1 proteins by broadly neutralizing antibodies
WO2013055908A1 (fr) 2011-10-12 2013-04-18 The Scripps Research Institute Mini boucle v3 de gp120 du vih-1 et ses utilisations
US9683268B2 (en) 2012-09-19 2017-06-20 Beth Israel Deaconess Viruses associated with immunodeficiency and enteropathy and methods using same
SG11201503864TA (en) 2012-11-16 2015-06-29 Beth Israel Hospital Recombinant adenoviruses and use thereof
CA2897059C (fr) 2013-01-07 2021-12-28 Beth Israel Deaconess Medical Center, Inc. Vaccins de trimere d'enveloppe (env) de virus d'immunodeficience humaine (vih) stabilises et procedes d'utilisation de ceux-ci
AU2014289274B2 (en) 2013-07-08 2018-11-15 Brandeis University Rotavirus particles with chimeric surface proteins
US10376583B2 (en) 2013-09-30 2019-08-13 Beth Israel Deaconess Medical Center, Inc. Human immunodeficiency virus therapies utilizing N332-glycan-dependent antibodies and a reservoir activator

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4603112A (en) 1981-12-24 1986-07-29 Health Research, Incorporated Modified vaccinia virus
US5639649A (en) 1989-01-18 1997-06-17 Brtish Technology Group Limited Attenuated viruses
US5762938A (en) 1991-03-07 1998-06-09 Virogenetics Corporation Modified recombinant vaccinia virus and expression vectors thereof
US5643576A (en) 1994-05-27 1997-07-01 The University Of North Carolina At Chapel Hill Method of inducing an immune response with a live Venezuelan Equine Encephalitis virus expressing a heterologous immunogen
US7592014B2 (en) * 1999-06-25 2009-09-22 Progenics Pharmaceuticals Inc. Stabilized viral envelope proteins and uses thereof
WO2006040330A2 (fr) 2004-10-13 2006-04-20 Crucell Holland B.V. Vecteurs adenoviraux ameliores et leurs utilisations
WO2007024941A2 (fr) 2005-08-23 2007-03-01 The Regents Of The University Of California Vaccin polyvalent
WO2007104792A2 (fr) 2006-03-16 2007-09-20 Crucell Holland B.V. Adénovirus recombinés basés sur les sérotypes 26 et 48 et utilisation de ceux-ci
US20110250220A1 (en) * 2006-10-23 2011-10-13 PROGENICS PHARMACEUTICAL: INC.: and CORNELL RESEARCH FOUNDATION INC. Modified gp140 envelope polypeptides of hiv-1 isolates, compositions, stabilized trimeric complexes, and uses thereof
US20120045472A1 (en) * 2008-10-10 2012-02-23 Beth Israel Deaconess Medical Center Biochemically Stabilized HIV-1 ENV Trimer Vaccine
WO2010059732A1 (fr) 2008-11-18 2010-05-27 Beth Israel Deaconess Medical Center Vaccins antiviraux présentant une immunogénicité cellulaire améliorée
US20120076812A1 (en) 2008-11-18 2012-03-29 Barouch Dan H Antiviral vaccines with improved cellular immunogenicity
WO2012030904A2 (fr) 2010-08-31 2012-03-08 Theraclone Sciences, Inc. Anticorps neutralisants anti-virus de l'immunodéficience humaine (vih)
WO2015048779A1 (fr) 2013-09-30 2015-04-02 Qualcomm Incorporated Communication par paquet court dans un réseau sur courants porteurs
WO2015051270A1 (fr) 2013-10-04 2015-04-09 Beth Israel Deaconess Medical Center, Inc. Vaccins de trimères d'enveloppe (env) de clade c du virus de l'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci

Non-Patent Citations (50)

* Cited by examiner, † Cited by third party
Title
BAROUCH ET AL., CELL., vol. 155, 2013, pages 531
BAROUCH ET AL., NAT. MED., vol. 16, 2010, pages 324
BAROUCH ET AL., NATURE., vol. 503, 2013, pages 224
BAROUCH, NATURE., vol. 455, 2008, pages 613
CARDOSO ET AL., J. MOL. BIOL., vol. 365, 2007, pages 1533
CASADEVALL, NAT. BIOTECHNOL., vol. 20, 2002, pages 114
CHEN ET AL., NATURE, vol. 433, 2005, pages 834
COHEN, SCIENCE, vol. 259, 1993, pages 1691 - 1692
EDMONDS ET AL., VIROLOGY, vol. 408, 2010, pages 1
ENGELHARDT ET AL., PROC. NATL. ACAD. SCI. USA, vol. 91, 1994, pages 6196
FISCHER ET AL., NAT. MED., vol. 13, 2007, pages 100
FISHER ET AL.: "Polyvalent Vaccine for Optimal Coverage of Potential T-Cell Epitopes in Global HIV-1 Variants", NAT. MED., vol. 13, no. 1, 2007, pages 100 - 106, XP007911386, DOI: 10.1038/nm1461
FREEMAN ET AL., STRUCTURE., vol. 18, 2010, pages 1632
FREY ET AL., NAT. STRUCT. MOL. BIOL., vol. 17, 2010, pages 1486
FREY ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 105, 2008, pages 3739
FYNAN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 11478
IGARASHI ET AL., NAT. MED., vol. 5, 1999, pages 211 - 16
JULIEN ET AL., SCIENCE., vol. 342, 2013, pages 1477
KALISH ET AL., AIDS., vol. 9, 1995, pages 851
KARLSSON HEDESTAM ET AL., NAT. REV. MICROBIOL., vol. 6, 2008, pages 143
KELLER ET AL., CLIN. MICROBIOL. REV., vol. 13, 2000, pages 602 - 14
KOCHANEK ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 5731
KORBER ET AL., BR. MED. BULL., vol. 58, 2001, pages 19
KOVACS ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 109, 2012, pages 12111
KWONG ET AL., NATURE, vol. 393, 1998, pages 648
LOANNOU ET AL., J. VIROL., vol. 76, 2002, pages 9002
LOUWAGIE ET AL., J. VIROL., vol. 69, 1995, pages 263
MANGEATTRONO, HUMAN GENE THERAPY, vol. 16, no. 8, 2005, pages 913
MASCOLA ET AL., ANNU. REV. IMMUNOL., vol. 28, 2010, pages 413
MASCOLA ET AL., J. VIROL., vol. 79, 2005, pages 10103
MCLELLAN ET AL., NATURE., vol. 480, 2011, pages 336
MONTEFIORI, CURR. PROT. IMMUNOL. CHAPTER, vol. 12, 2005, pages 1211
MONTEFIORI, METHODS MOL. BIOL., vol. 485, 2009, pages 395
MONTEFIORI, METHODS. MOL. BIOL., vol. 485, 2009, pages 395
NKOLOLA ET AL., J. VIROL., vol. 84, 2010, pages 3270
NKOLOLA ET AL.: "Breadth of Neutralizing Antibodies Elicited by Stable, Homogeneous Clade A and Clade C HIV-1 gp140 Envelope Trimers in Guinea Pigs'.", JOURNAL OF VIROLOGY., vol. 84, no. 7., 6 January 2010 (2010-01-06), pages 3270 - 3279, XP055083632 *
OFEK ET AL., J. VIROL., vol. 78, 2004, pages 10724
PEJCHAL ET AL., SCIENCE., vol. 334, 2011, pages 1097
POLONIS ET AL., VIROLOGY, vol. 375, 2008, pages 315
SANDERS ET AL., PLOS PATHOG, vol. 9, 2013, pages e1003618
SANTRA, VIROLOGY., vol. 428, 2012, pages 121
See also references of EP2983686A4
SRIVASTAVA ET AL., HUM. VACCIN., vol. 1, 2005, pages 45
STAMATATOS ET AL., NAT. MED., vol. 15, 2009, pages 866
STEPHENSON ET AL., J. VIROL., vol. 86, 2012, pages 11434
STEPHENSON, IMMUNOL. REV., vol. 254, 2013, pages 295
WALKER ET AL., SCIENCE., vol. 326, 2009, pages 285
WIZNEROWICZTRONO, TRENDS BIOTECHNOL., vol. 23, no. 1, 2005, pages 42
WOLFF ET AL., BIOTECHNIQUES, vol. 11, 1991, pages 474485
WU ET AL., SCIENCE., vol. 329, 2010, pages 856

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10653770B2 (en) * 2008-10-10 2020-05-19 Beth Israel Deaconess Medical Center, Inc. Biochemically stabilized HIV-1 Env trimer vaccine
KR101971808B1 (ko) * 2014-09-26 2019-04-23 베쓰 이스라엘 디코니스 메디칼 센터 인크 인간 면역 결핍 바이러스 감염에 대한 방어 면역을 유도하기 위한 방법 및 조성물
CN106999571B (zh) * 2014-09-26 2020-10-02 贝斯以色列护理医疗中心有限公司 诱导针对人免疫缺陷病毒感染的保护性免疫性的方法和组合物
JP2017531627A (ja) * 2014-09-26 2017-10-26 ベス イスラエル ディーコネス メディカル センター インコーポレイテッド ヒト免疫不全ウイルス感染に対する防御免疫を誘導するための方法および組成物
WO2016049287A1 (fr) 2014-09-26 2016-03-31 Beth Israel Deaconess Medical Center, Inc. Méthodes et compositions d'induction d'une immunité protectrice contre l'infection par le virus de l'immunodéficience humaine
CN112121160A (zh) * 2014-09-26 2020-12-25 贝斯以色列护理医疗中心有限公司 诱导针对人免疫缺陷病毒感染的保护性免疫性的方法和组合物
EP3197489A4 (fr) * 2014-09-26 2018-03-14 Beth Israel Deaconess Medical Center, Inc. Méthodes et compositions d'induction d'une immunité protectrice contre l'infection par le virus de l'immunodéficience humaine
US20180250385A1 (en) * 2014-09-26 2018-09-06 Janssen Vaccines & Prevention B.V. Methods for inducing protective immunity against human immunodeficiency virus infection
US10137191B2 (en) 2014-09-26 2018-11-27 Janssen Vaccines & Prevention B.V. Methods and compositions for inducing protective immunity against human immunodeficiency virus infection
AU2015320574B2 (en) * 2014-09-26 2018-12-06 Beth Israel Deaconess Medical Center, Inc. Methods and compositions for inducing protective immunity against Human Immunodeficiency Virus infection
KR102159626B1 (ko) * 2014-09-26 2020-09-25 베쓰 이스라엘 디코니스 메디칼 센터 인크 인간 면역 결핍 바이러스 감염에 대한 방어 면역을 유도하기 위한 방법 및 조성물
KR20170066454A (ko) * 2014-09-26 2017-06-14 베쓰 이스라엘 디코니스 메디칼 센터 인크 인간 면역 결핍 바이러스 감염에 대한 방어 면역을 유도하기 위한 방법 및 조성물
EA037583B1 (ru) * 2014-09-26 2021-04-16 Бет Изрейэл Диконисс Медикал Сентер, Инк. Способы и композиции для индукции защитного иммунитета против инфекции вирусом иммунодефицита человека
AU2018267669B2 (en) * 2014-09-26 2020-03-05 Beth Israel Deaconess Medical Center, Inc. Methods and compositions for inducing protective immunity against human immunodeficiency virus infection
CN106999571A (zh) * 2014-09-26 2017-08-01 贝斯以色列护理医疗中心有限公司 诱导针对人免疫缺陷病毒感染的保护性免疫性的方法和组合物
US10471137B2 (en) 2014-09-26 2019-11-12 Janssen Vaccines & Prevention B.V. Methods for inducing protective immunity against human immunodeficiency virus infection
EP3868398A1 (fr) 2014-09-26 2021-08-25 Beth Israel Deaconess Medical Center, Inc. Méthodes et compositions d'induction d'une immunité protectrice contre l'infection par le virus de l'immunodéficience humaine
US11207400B2 (en) 2014-09-26 2021-12-28 Janssen Vaccines & Prevention B.V. Compositions and methods for inducing protective immunity against human immunodeficiency virus infection
KR20190042736A (ko) * 2014-09-26 2019-04-24 베쓰 이스라엘 디코니스 메디칼 센터 인크 인간 면역 결핍 바이러스 감염에 대한 방어 면역을 유도하기 위한 방법 및 조성물
US10894078B2 (en) 2014-10-03 2021-01-19 Vir Biotechnology, Inc. HIV vaccines comprising one or more population episensus antigens
US11554168B2 (en) 2014-10-03 2023-01-17 Vir Biotechnology, Inc. HIV vaccines comprising one or more population episensus antigens
US11628215B2 (en) 2014-10-03 2023-04-18 Vir Biotechnology, Inc. HIV vaccines comprising one or more population episensus antigens
KR102633096B1 (ko) 2014-10-03 2024-02-02 트리아드 내셔널 시큐리티, 엘엘씨 하나 이상의 집단 에피센서스 항원을 포함하는 hiv 백신 조성물
KR20170122711A (ko) * 2014-10-03 2017-11-06 로스 알라모스 내셔널 씨큐어리티 엘엘씨 하나 이상의 집단 에피센서스 항원을 포함하는 hiv 백신 조성물
US10369214B2 (en) 2015-12-15 2019-08-06 Janssen Vaccines & Prevention B.V. Synthetic human immunodeficiency virus (HIV) envelope antigen, vectors, and compositions thereof
EP3584252A1 (fr) 2015-12-15 2019-12-25 Janssen Vaccines & Prevention B.V. Antigènes, vecteurs, compositions du virus de l'immunodéficience humaine et leurs procédés d'utilisation
EP3964569A1 (fr) 2015-12-15 2022-03-09 Janssen Vaccines & Prevention B.V. Antigènes, vecteurs, compositions du virus de l'immunodéficience humaine et leurs procédés d'utilisation
US11896663B2 (en) 2015-12-15 2024-02-13 Janssen Vaccines & Prevention B.V. Immunodeficiency virus type 1 (HIV-1) mutant envelope proteins
US10973907B2 (en) 2015-12-15 2021-04-13 Janssen Vaccines & Prevention B.V. Recombinant adenoviruses encoding mosaic human immunodeficiency virus (HIV) Env, Gag, and Pol antigens
AU2017286375B2 (en) * 2016-06-16 2019-04-18 Janssen Vaccines & Prevention B.V. HIV vaccine formulation
US10273268B2 (en) 2016-06-16 2019-04-30 Janssen Vaccines & Prevention B.V. HIV vaccine formulation
US10934328B2 (en) 2016-06-16 2021-03-02 Janssen Vaccines & Prevention B.V. HIV vaccine formulation
WO2017216288A1 (fr) 2016-06-16 2017-12-21 Janssen Vaccines & Prevention B.V. Formulation de vaccin contre le vih
US11603389B2 (en) 2016-06-16 2023-03-14 Janssen Vaccines & Prevention B.V. HIV vaccine formulation
US10525123B2 (en) 2016-09-02 2020-01-07 Janssen Vaccines & Prevention B.V. Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment
US10307477B2 (en) 2016-09-02 2019-06-04 Janssen Vaccines & Prevention B.V. Methods for inducing an immune response against human immunodeficiency virus infection in subjects undergoing antiretroviral treatment
US10793607B2 (en) 2016-09-15 2020-10-06 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
US11820796B2 (en) 2016-09-15 2023-11-21 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
US11365222B2 (en) 2016-09-15 2022-06-21 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
US11723970B2 (en) 2017-06-15 2023-08-15 Janssen Vaccines & Prevention B. V. Poxvirus vectors encoding HIV antigens, and methods of use thereof
US11229693B2 (en) 2017-06-15 2022-01-25 Janssen Vaccines & Prevention B.V. Poxvirus vectors encoding HIV antigens, and methods of use thereof
WO2018229711A1 (fr) 2017-06-15 2018-12-20 Janssen Vaccines & Prevention B.V. Vecteurs à poxvirus codant pour des antigènes du vih, et leurs procédés d'utilisation
US11732010B2 (en) 2017-07-19 2023-08-22 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
US10968254B2 (en) 2017-07-19 2021-04-06 Janssen Vaccines & Prevention B.V. Trimer stabilizing HIV envelope protein mutations
WO2019018724A1 (fr) 2017-07-21 2019-01-24 Janssen Vaccines & Prevention B.V. Procédés d'induction sûre d'une immunité croisée multiclades contre une infection par le virus de l'immunodéficience humaine chez l'être humain
WO2019055888A1 (fr) 2017-09-18 2019-03-21 Janssen Vaccines & Prevention B.V. Méthodes pour induire une réponse immunitaire contre une infection par le virus de l'immunodéficience humaine chez des sujets subissant un traitement antirétroviral
US11517618B2 (en) 2018-09-25 2022-12-06 Janssen Vaccines & Prevention B.V. Method of inducing an immune response against human immunodeficiency virus by co-localized administration of vaccine components
WO2020064621A1 (fr) 2018-09-25 2020-04-02 Janssen Vaccines & Prevention B.V. Méthode d'induction d'une réponse immunitaire contre le virus de l'immunodéficience humaine par administration co-localisée de composants vaccinaux
WO2020237052A1 (fr) 2019-05-22 2020-11-26 Janssen Vaccines & Prevention B.V. Procédés pour induire une réponse immunitaire contre une infection par le virus de l'immunodéficience humaine chez des sujets suivant un traitement antirétroviral
WO2021089770A2 (fr) 2019-11-07 2021-05-14 Janssen Vaccines & Prevention B.V. Purification de protéines
US11857619B2 (en) 2019-11-07 2024-01-02 Janssen Vaccines & Prevention B.V. Multimodal chromatography method for the purification of HIV-1 envelope glycoprotein
WO2023198815A1 (fr) 2022-04-14 2023-10-19 Janssen Vaccines & Prevention B.V. Administration séquentielle d'adénovirus

Also Published As

Publication number Publication date
EP2983686A4 (fr) 2016-09-14
US9932370B2 (en) 2018-04-03
EA201591287A1 (ru) 2015-12-30
SG11201505229XA (en) 2015-08-28
US20210317169A1 (en) 2021-10-14
KR20150118131A (ko) 2015-10-21
CN105263506B (zh) 2018-03-09
HK1214509A1 (zh) 2016-07-29
JP6357487B2 (ja) 2018-07-11
PH12015501526A1 (en) 2015-09-21
US20140302080A1 (en) 2014-10-09
AU2018200696A1 (en) 2018-02-22
US20180186839A1 (en) 2018-07-05
JP2016503819A (ja) 2016-02-08
AP2015008634A0 (en) 2015-07-31
IL239805A (en) 2017-11-30
CN105263506A (zh) 2016-01-20
SG10201705880QA (en) 2017-08-30
AU2014203886A1 (en) 2015-08-20
US11059863B2 (en) 2021-07-13
NZ710727A (en) 2020-03-27
IL239805A0 (en) 2015-08-31
MY187152A (en) 2021-09-06
CA2897059A1 (fr) 2014-07-10
US20190055290A1 (en) 2019-02-21
PH12015501526B1 (en) 2015-09-21
CA2897059C (fr) 2021-12-28
MX2015008815A (es) 2016-10-26
EA030983B1 (ru) 2018-10-31
KR102020758B1 (ko) 2019-09-11
ZA201505608B (en) 2018-11-28
US10160788B2 (en) 2018-12-25
AU2018200696B2 (en) 2019-09-12
AU2014203886B2 (en) 2017-11-02
EP2983686A1 (fr) 2016-02-17

Similar Documents

Publication Publication Date Title
AU2018200696B2 (en) Stabilized human immunodeficiency virus (hiv) envelope (env) trimer vaccines and methods of using the same
JP6959289B2 (ja) ヒト免疫不全ウイルス抗原、ベクター、組成物、およびその使用方法
EP3052518B1 (fr) Vaccins de trimères d'enveloppe (env) de clade c du virus de l'immunodéficience humaine (vih) stabilisés et procédés d'utilisation de ceux-ci
US11230572B2 (en) Signature-based human immunodeficiency virus (HIV) envelope (Env) trimer vaccines and methods of using the same
JP2009539353A (ja) Ｈｉｖ−１クレイドａのコンセンサス配列、抗原及びトランス遺伝子
CN112770770A (zh) 共定位施用疫苗组分诱导针对人类免疫缺陷病毒的免疫应答的方法
OA17893A (en) Stabilized human immunodeficiency virus (HIV) envelope (Env) trimer vaccines and methods of using the same.
WO2005047483A2 (fr) Renta: un immunogene du vih, et utilisations de renta
Tarrés i Freixas HIV-1 Virus-Like Particles engineered to display a high antigen density. Preclinical development of a versatile vaccine platform

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201480012440.7

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14735323

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2897059

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2015551842

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 239805

Country of ref document: IL

Ref document number: MX/A/2015/008815

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015016263

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: IDP00201504770

Country of ref document: ID

WWE Wipo information: entry into national phase

Ref document number: 201591287

Country of ref document: EA

Ref document number: 2014735323

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20157021492

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2014203886

Country of ref document: AU

Date of ref document: 20140107

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112015016263

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150706